Antioxidant activity of ebselen and related selenoorganic compounds in microsomal lipid peroxidation.
Ebselen, 2-phenyl-1,2-benzisoselenazol-3(2H)one, and its derivatives were compared for their ability to protect microsomal membranes against iron/ADP/ascorbate-induced lipid peroxidation, measured as low-level chemiluminescence and accumulation of thiobarbituric acid-reactive substances (TBARS). The concentrations of the compounds required to double the lag time of the control with no added antioxidants were 0.13 microM for ebselen, 0.5 microM for the N-pyridyl analog, 0.3-0.7 microM for the selenylsulfides, about 1.0 microM for the selenoxide derivative and 2.0 microM for the sulfur analog of ebselen. The open-chain seleno- and thioether derivatives, on the other hand, exhibited comparatively low abilities to protect the membrane, the lag doubling concentrations for these compounds being 100-1,000 fold higher than that for ebselen. The rate of loss of alpha-tocopherol in the microsomal membrane during peroxidation was significantly diminished in the presence of 0.1-0.5 microM ebselen, while the glutathione adduct of ebselen was equally effective in protecting the loss of alpha-tocopherol. The sulphur analogue and, the benzylated and methylated derivatives of ebselen did not afford protection. Ebselen was without effect in microsomes from vitamin E-deficient rats up to 20 microM, indicative of the dependence of its protective ability upon alpha-tocopherol.
Narayanaswami
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Institut für Physiologische Chemie I, Universität Düsseldorf, W. Germany.
Sies
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D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D001393:Azoles / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism; D007501:Iron / Q000494:pharmacology; D054833:Isoindoles; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects*; D008163:Luminescent Measurements; D008297:Male; D008861:Microsomes / Q000378:metabolism* / Q000648:ultrastructure; D016566:Organoselenium Compounds; D051381:Rats; D011919:Rats, Inbred Strains; D012643:Selenium / Q000494:pharmacology*; D013858:Thiobarbiturates; D014810:Vitamin E / Q000378:metabolism
D000975:Antioxidants; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; D013858:Thiobarbiturates; D014810:Vitamin E; C042986:ebselen; D000244:Adenosine Diphosphate; D007501:Iron; D012643:Selenium; C029684:thiobarbituric acid; D001205:Ascorbic Acid